Invited Presentation 36th Lorne Cancer Conference 2024

Blocking cancer-fibroblast mutualism inhibits estrogen-independent proliferation of endocrine therapy-resistant breast cancer (#6)

Andrea Bild 1
  1. City of Hope Comprehensive Cancer Center, South Pasadena, CA, United States

Endocrine resistance, a major clinical hurdle for breast cancer patients, arises as cancer cells evolve to thrive without estrogen. Our study breaks new ground in understanding this phenomenon by identifying the nature and source of the growth signals in patient tumors that drive such proliferation and pinpointing therapeutic targets for these resilient cancer cell phenotypes. By modeling the phenotypes in single-cell tumor data from breast cancer patients before and during treatment with endocrine therapy, we found that in many stage II/III tumors, the shift to estrogen-independence is predominantly fueled by the activation of the ERBB pathway. In response to treatment, these resistant cancer cells increase ERBB growth factor receptors and amplify communication with nearby fibroblasts via heightened TGFβ signaling. This interaction prompts fibroblasts to differentiate into a more proliferative and mesenchymal state, resulting in higher production of ERBB growth factors. This mutualistic relationship fosters a tumor microenvironment rich in growth factors, enabling cancer cells to circumvent the need for estrogen and evade endocrine therapy. These findings were validated in an independent clinical study and through multiple in vitro models, emphasizing their clinical significance and therapeutic potential. In laboratory experiments, we demonstrated that pan-ERBB inhibitors effectively disrupt the interaction between cancer cells and fibroblasts, halting the growth of resistant cells. This suggests a novel treatment strategy for endocrine-resistant ER+ breast cancer, focusing on altering cell interactions and the tumor microenvironment. Our study not only provides a deeper understanding of endocrine resistance but also opens new avenues for targeted therapy in breast cancer.